PROJECT SUMMARY Inflammation is recognized as a major underlying mechanism for a number of diseases with an environmental etiology that have serious pathologic outcomes such as autoimmunity, cancer, cardiovascular disease, lung disease, neurodegeneration as examples. Mast cells represent a major sensory arm of the body's innate immune system by functioning as environmental `sensors' to communicate with other physiological and/or immune responses due to their widespread tissue presence at mucosal surfaces, near blood vessels and the nervous system. Through funding from R01 ES019311, we have begun to unravel novel mechanisms of non- IgE mast cell activation that contribute to inflammation. While mast cells are implicated as pathogenic in a number of diseases beyond allergy little is known on mechanisms and even less is known regarding how environmental toxicants trigger mast cell responses that contribute to these disease outcomes. Therefore, our overarching research goal has been focused on delineating the role of mast cells in environmental health through better understanding of their role as first responders in environmental insult, resulting effects on innate and adaptive immunity, and their communication with other cells and physiological systems. Our research has uncovered novel non-IgE mediated mechanisms of mast cell activation driven by particulates (e.g. nanoparticles, air pollution particulate matter, silica, etc) that contributes to adverse outcomes in the pulmonary and cardiovascular system. In addition, through genome wide association studies using the hybrid mouse diversity panel as well as transcriptomics studies we have uncovered novel genetic regulation of non-IgE mast cell activation driven by particulates. In particular, we have found a regulatory role for thioredoxin interacting protein (Txnip) in non-IgE mast cell activation. In this proposal, we will investigate both redox-independent and -dependent Txnip regulation of mast cell activation by environmental particulates (nanoparticles and ambient particulate matter) and its influence on G protein-coupled receptors, glycolysis, redox regulation and granule exocytosis. In addition, we will investigate the role of Txnip using mast cells from patients with chronic idiopathic urticaria (a mast cell activation disorder largely driven by non-IgE mechanisms and which is thought to be triggered by environmental exposures). Our overall goal is to delineate the role mast cells in environmental health through better understanding of their role as first responders in environmental insult, their activation by particulates and novel mechanisms of non-IgE activation that contributes to disease outcomes.